Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Coronal Cementum and Reduced Enamel Epithelium on Occlusal Surface of Impacted Wisdom Tooth in a Human

Naohiro Horie, Masaru Murata, Yasuhito Minamida, Hiroki Nagayasu, Tsuyoshi Shimo, Toshiyuki Akazawa, Hidetsugu Tsujigiwa, Youssef Haikel, Hitoshi Nagatsuka

Dentistry Journal 12 ( 11 ) 348 - 348 2024.10

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Background: There is only limited research on the coronal cementum of a tooth, and the mechanisms of its forming process are not well-defined. This report presents a coronal cementum on the occlusal surfaces of enamel in an impacted wisdom tooth in a human, which is not nearly the cervical portion. Materials and Methods: The tooth (Tooth #1) was derived from a 46-year-old female. Histological analysis, including hematoxylin and eosin (HE) and toluidine blue (TB) staining, and Scanning Electron Microscopy and Energy Dispersive X-ray Spectrometer (SEM-EDS) analysis of the extracted tooth were conducted. Radiographic examination showed that Tooth #1 was horizontally impacted in the maxilla and had the apex of a single root placed between the buccal and palatal roots of Tooth #2. Results: Coronal cementum was distributed widely on the enamel, and reduced enamel epithelium was also found with enamel matrix proteins histologically. The formation of acellular cementum was observed to be more predominant than that of the cellular cementum in Tooth #1. SEM showed that the occlusal cementum connected directly with enamel. Calcium mapping revealed an almost similar occlusal cementum and enamel. In addition, the spectrum of elements in coronal cementum resembled the primary cementum according to SEM-EDS. Discussion: Thus, coronal cementogenesis in impacted human teeth might be related to the existence of reduced enamel epithelium.

DOI： 10.3390/dj12110348

Histological differences related to autophagy in the minor salivary gland between primary and secondary types of Sjögren's syndrome. Reviewed International journal

Hitomi Ono-Minagi, Tsutomu Nohno, Kiyofumi Takabatake, Takehiro Tanaka, Takayuki Katsuyama, Kohta Miyawaki, Jun Wada, Soichiro Ibaragi, Seiji Iida, Tadashi Yoshino, Hitoshi Nagatsuka, Takayoshi Sakai, Hideyo Ohuchi

BMC oral health 24 ( 1 ) 1099 - 1099 2024.9

Language：English Publishing type：Research paper (scientific journal)

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging.

DOI： 10.1186/s12903-024-04869-4

Risk factors for post-extraction infection of mandibular third molar: A retrospective clinical study. Reviewed International journal

Yumika Mukainaka, Shintaro Sukegawa, Hotaka Kawai, Tetsuya Nishida, Minoru Miyake, Hitoshi Nagatsuka

Journal of stomatology, oral and maxillofacial surgery 125 ( 4S ) 101841 - 101841 2024.9

Language：English Publishing type：Research paper (scientific journal)

Post-extraction infection is one of the most concerning complications of mandibular third molar extraction, which is the most common procedure in oral and maxillofacial surgery. We investigated risk factors for post-extraction infection by retrospectively analyzing 2,513 teeth/cases of mandibular third molar extraction (1,040 males, 1,473 females) performed at a single medical facility in Kobe, Japan from January 2014 to May 2022. The predictive variables were categorized as patient attributes, health status, and anatomic, pathological, and operative variables that may be associated with post-extraction infection. The outcome variable was the post-extraction infection rate. The post-extraction infection rate was 5.73 % (144 of the 2,513 teeth), and the mean age of the patients with a post-extraction infection was 41.76 ± 16.8 years. Our analyses also revealed that the postoperative infection rate was significantly increased in patients aged ≥36 years. A multivariate logistic regression analysis showed that the following variables were significantly associated with post-extraction infection: preoperative antibiotic administration (odds ratio [OR] 4.68, p < 0.001), postoperative paresthesia of the inferior alveolar nerve (OR 4.34, p < 0.001), intraoperative hemostatic procedure (OR 1. 74, p = 0.008), position of Pell and Gregory classifications (OR 1. 70, p < 0.001), Winter's classification (OR 1.28, p < 0.03), and age (OR 1.03, p < 0.001). Oral and maxillofacial surgeons should be aware of these risk factors.

DOI： 10.1016/j.jormas.2024.101841

Effect of Scaffold Geometrical Structure on Macrophage Polarization during Bone Regeneration Using Honeycomb Tricalcium Phosphate. Reviewed International journal

Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Anqi Chang, Tianyan Piao, Yasunori Inada, Takuma Arashima, Ayumi Morimatsu, Ayumi Tanaka, Hotaka Kawai, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 17 ( 16 ) 2024.8

Language：English Publishing type：Research paper (scientific journal)

The polarization balance of M1/M2 macrophages with different functions is important in osteogenesis and bone repair processes. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which is a cylindrical scaffold with a honeycomb arrangement of straight pores, and we demonstrated that TCP with 300 and 500 μm pore diameters (300TCP and 500TCP) induced bone formation within the pores. However, the details of the influence of macrophage polarization on bone formation using engineered biomaterials, especially with respect to the geometric structure of the artificial biomaterials, are unknown. In this study, we examined whether differences in bone tissue formation due to differences in TCP geometry were due to the polarity of the assembling macrophages. Immunohistochemistry for IBA-1, iNOS, and CD163 single staining was performed. The 300TCP showed a marked infiltration of iNOS-positive cells, which are thought to be M1 macrophages, during the osteogenesis process, while no involvement of CD163-positive cells, which are thought to be M2 macrophages, was observed in the TCP pores. In addition, 500TCP showed a clustering of iNOS-positive cells and CD163-positive cells at 2 weeks, suggesting the involvement of M2 macrophages in the formation of bone tissue in the TCP pores. In conclusion, we demonstrated for the first time that the geometrical structure of the artificial biomaterial, i.e., the pore size of honeycomb TCP, affects the polarization of M1/2 macrophages and bone tissue formation in TCP pores.

DOI： 10.3390/ma17164108

Training high-performance deep learning classifier for diagnosis in oral cytology using diverse annotations. Reviewed International journal

Shintaro Sukegawa, Futa Tanaka, Keisuke Nakano, Takeshi Hara, Takanaga Ochiai, Katsumitsu Shimada, Yuta Inoue, Yoshihiro Taki, Fumi Nakai, Yasuhiro Nakai, Takanori Ishihama, Ryo Miyazaki, Satoshi Murakami, Hitoshi Nagatsuka, Minoru Miyake

Scientific reports 14 ( 1 ) 17591 - 17591 2024.7

Language：English Publishing type：Research paper (scientific journal)

The uncertainty of true labels in medical images hinders diagnosis owing to the variability across professionals when applying deep learning models. We used deep learning to obtain an optimal convolutional neural network (CNN) by adequately annotating data for oral exfoliative cytology considering labels from multiple oral pathologists. Six whole-slide images were processed using QuPath for segmenting them into tiles. The images were labeled by three oral pathologists, resulting in 14,535 images with the corresponding pathologists' annotations. Data from three pathologists who provided the same diagnosis were labeled as ground truth (GT) and used for testing. We investigated six models trained using the annotations of (1) pathologist A, (2) pathologist B, (3) pathologist C, (4) GT, (5) majority voting, and (6) a probabilistic model. We divided the test by cross-validation per slide dataset and examined the classification performance of the CNN with a ResNet50 baseline. Statistical evaluation was performed repeatedly and independently using every slide 10 times as test data. For the area under the curve, three cases showed the highest values (0.861, 0.955, and 0.991) for the probabilistic model. Regarding accuracy, two cases showed the highest values (0.988 and 0.967). For the models using the pathologists and GT annotations, many slides showed very low accuracy and large variations across tests. Hence, the classifier trained with probabilistic labels provided the optimal CNN for oral exfoliative cytology considering diagnoses from multiple pathologists. These results may lead to trusted medical artificial intelligence solutions that reflect diverse diagnoses of various professionals.

DOI： 10.1038/s41598-024-67879-w

【頭頸部腫瘍II-上気道・口腔・顎顔面骨腫瘍-】口腔・歯原性・顎顔面骨腫瘍のWHO分類改訂のポイント

中野敬介, 長塚仁

病理と臨床 42 ( 7 ) 0670 - 0675 2024.7

Efficacy of Cisplatin–CXCR4 Antagonist Combination Therapy in Oral Cancer Reviewed International journal

Saori Yoshida, Hotaka Kawai, Yamin Soe, Htoo Shwe Eain, Sho Sanou, Kiyofumi Takabatake, Yohei Takeshita, Miki Hisatomi, Hitoshi Nagatsuka, Junichi Asaumi, Yoshinobu Yanagi

Cancers 16 ( 13 ) 2326 - 2326 2024.6

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin–AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.

DOI： 10.3390/cancers16132326

Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma. Reviewed International journal

Htoo Shwe Eain, Hotaka Kawai, Masaaki Nakayama, May Wathone Oo, Toshiaki Ohara, Yoko Fukuhara, Kiyofumi Takabatake, Quisheng Shan, Yamin Soe, Kisho Ono, Keisuke Nakano, Nobuyoshi Mizukawa, Seiji Iida, Hitoshi Nagatsuka

JCI insight 9 ( 10 ) 2024.5

Language：English Publishing type：Research paper (scientific journal)

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.

DOI： 10.1172/jci.insight.174618

[secondary publication] Management of odontogenic foci of infection(dental caries, periodontal disease and odontogenic infections) in the oral functional management of patients receiving cancer treatments: Guidelines based on a systematic review: A secondary publication(translation) of a primary publication(タイトル和訳中) Reviewed

Kurita Hiroshi, Umeda Masahiro, Ueno Takaaki, Uzawa Narikazu, Shibuya Yasuyuki, Nakamura Norifumi, Nagatsuka Hitoshi, Hayashi Takafumi, Mizoguchi Itaru, Tomihara Kei, Ikegami Yumiko, Noguchi Kazuma, Takiguchi Yuichi, Yamamoto Nobuyuki, Sakai Hironori

Oral Science International 21 ( 2 ) 161 - 180 2024.5

口腔扁平上皮癌に対する骨髄由来間葉系幹細胞の役割

佐能彰, 河合穂高, 高畠清文, 中野啓介, 長塚仁, 伊原木聰一郎

頭頸部癌 50 ( 2 ) 217 - 217 2024.5

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis Reviewed International journal

Sawako Ono, Katsutoshi Hirose, Shintaro Sukegawa, Kyoichi Obata, Masanori Masui, Kazuaki Hasegawa, Ai Fujimura, Katsumitsu Shimada, Satoko Nakamura, Akari Teramoto, Yumiko Hori, Eiichi Morii, Daisuke Motooka, Takuro Igawa, Takehiro Tanaka, Hitoshi Nagatsuka, Satoru Toyosawa, Hidetaka Yamamoto

Diagnostic Pathology 19 ( 1 ) 63 - 63 2024.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology.

Methods

Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes.

Results

We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1–4) were one woman and three men with a mean age of 53.75 years (range: 15–74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1–3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases.

Conclusions

We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated.

DOI： 10.1186/s13000-024-01487-0

Other Link： https://link.springer.com/article/10.1186/s13000-024-01487-0/fulltext.html

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system. Reviewed International journal

Tatsuo Ogawa, Kisho Ono, Shoji Ryumon, Hotaka Kawai, Tomoya Nakamura, Koki Umemori, Kunihiro Yoshida, Hideka Kanemoto, Kyoichi Obata, Norie Yoshioka, Tatsuo Okui, Kuniaki Okamoto, Hitoshi Nagatsuka, Soichiro Ibaragi

Head & neck 46 ( 3 ) 636 - 650 2024.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP-resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC. METHODS: We established CDDP-resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression. RESULTS: The CDDP-resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell-killing effect. CONCLUSIONS: EVs were involved in the ATP7B-mediated mechanism underlying CDDP resistance. Further clarification of the EV-induced CDDP-resistance mechanism may lead to novel therapeutic strategies for HNSCC.

DOI： 10.1002/hed.27620

Transcutaneous carbon dioxide suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma. Reviewed International journal

Aki Sasaki, Daisuke Takeda, Hotaka Kawai, Yoshiaki Tadokoro, Aki Murakami, Nanae Yatagai, Satomi Arimoto, Hitoshi Nagatsuka, Masaya Akashi, Takumi Hasegawa

PloS one 19 ( 4 ) e0302194 2024

Language：English Publishing type：Research paper (scientific journal)

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

DOI： 10.1371/journal.pone.0302194

Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. Reviewed International journal

Kunihiro Yoshida, Kaung Htike, Takanori Eguchi, Hotaka Kawai, Htoo Shwe Eain, Manh Tien Tran, Chiharu Sogawa, Koki Umemori, Tatsuo Ogawa, Hideka Kanemoto, Kisho Ono, Hitoshi Nagatsuka, Akira Sasaki, Soichiro Ibaragi, Kuniaki Okamoto

Journal of oral biosciences 66 ( 1 ) 205 - 216 2023.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Rab11(Rab11a and Rab11b) localizes primarily along recycling endosomes in cells and is involved in various intracellular trafficking processes, including membrane receptor recycling and secretion of exosomes or small extracellular vesicles (EVs). Although Rab11 is closely associated with the progression and metastasis of various cancer types, little is known about Rab11' role in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the roles of Rab11a and Rab11b in HNSCC. METHODS: The clinical significance of Rab11 expression in HNSCC was investigated using a public database and tissue microarray analysis. Stable cell lines with loss and gain of Rab11a or Rab11b were originally established to investigate their roles in the proliferative, migratory, and invasive capabilities of HNSCC cells. RESULTS: Database analysis revealed a significant association between Rab11b mRNA expression and a favorable patient survival rate in HNSCC. Tissue microarray analysis revealed that Rab11b expression was the highest in normal tissues and gradually decreased across the stages of HNSCC progression. Overexpression of Rab11a or Rab11b resulted in a decrease in epidermal growth factor receptor (EGFR), Epithelial cell adhesion molecule (EpCAM) exosome secretion, and the migratory and invasive potential of HNSCC cells. The knockdown of Rab11a or Rab11b increased EpCAM/CD9 exosome secretion in addition to the migratory and invasive potential of HNSCC cells. CONCLUSIONS: Rab11 suppresses HNSCC by regulating EGFR recycling and EpCAM exosome secretion in HNSCC cells. Our results indicate that Rab11b is a superior prognostic indicator of HNSCC and holds promise for developing novel therapeutic strategies.

DOI： 10.1016/j.job.2023.11.007

Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report. Reviewed International journal

Yuki Shinoda-Ito, Anna Hirai, Kazuhiro Omori, Hidetaka Ideguchi, Hideki Yamamoto, Fumino Kato, Kyoichi Obata, Tatsuo Ogawa, Keisuke Nakano, Takato Nakadoi, Eri Katsuyama, Soichiro Ibaragi, Tadashi Yamamoto, Hitoshi Nagatsuka, Akira Hirasawa, Shogo Takashiba

BMC oral health 23 ( 1 ) 843 - 843 2023.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

DOI： 10.1186/s12903-023-03586-8

Effectiveness of deep learning classifiers in histopathological diagnosis of oral squamous cell carcinoma by pathologists. Reviewed International journal

Shintaro Sukegawa, Sawako Ono, Futa Tanaka, Yuta Inoue, Takeshi Hara, Kazumasa Yoshii, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Shimada Katsumitsu, Fumi Nakai, Yasuhiro Nakai, Ryo Miyazaki, Satoshi Murakami, Hitoshi Nagatsuka, Minoru Miyake

Scientific reports 13 ( 1 ) 11676 - 11676 2023.7

Language：English Publishing type：Research paper (scientific journal)

The study aims to identify histological classifiers from histopathological images of oral squamous cell carcinoma using convolutional neural network (CNN) deep learning models and shows how the results can improve diagnosis. Histopathological samples of oral squamous cell carcinoma were prepared by oral pathologists. Images were divided into tiles on a virtual slide, and labels (squamous cell carcinoma, normal, and others) were applied. VGG16 and ResNet50 with the optimizers stochastic gradient descent with momentum and spectral angle mapper (SAM) were used, with and without a learning rate scheduler. The conditions for achieving good CNN performances were identified by examining performance metrics. We used ROCAUC to statistically evaluate diagnostic performance improvement of six oral pathologists using the results from the selected CNN model for assisted diagnosis. VGG16 with SAM showed the best performance, with accuracy = 0.8622 and AUC = 0.9602. The diagnostic performances of the oral pathologists statistically significantly improved when the diagnostic results of the deep learning model were used as supplementary diagnoses (p-value = 0.031). By considering the learning results of deep learning model classifiers, the diagnostic accuracy of pathologists can be improved. This study contributes to the application of highly reliable deep learning models for oral pathological diagnosis.

DOI： 10.1038/s41598-023-38343-y

EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma. Reviewed International journal

Koki Umemori, Kisho Ono, Takanori Eguchi, Hotaka Kawai, Tomoya Nakamura, Tatsuo Ogawa, Kunihiro Yoshida, Hideka Kanemoto, Kohei Sato, Kyoichi Obata, Shoji Ryumon, Hirokazu Yutori, Naoki Katase, Tatsuo Okui, Hitoshi Nagatsuka, Soichiro Ibaragi

Oral oncology 142 106433 - 106433 2023.5

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance. MATERIALS AND METHODS: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS). RESULTS: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner. CONCLUSION: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab.

DOI： 10.1016/j.oraloncology.2023.106433

The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment. Reviewed International journal

Karnoon Shamsoon, Daichi Hiraki, Koki Yoshida, Kiyofumi Takabatake, Hiroaki Takebe, Kenji Yokozeki, Naohiro Horie, Naomasa Fujita, Nisrina Ekayani Nasrun, Tatsuo Okui, Hitoshi Nagatsuka, Yoshihiro Abiko, Akihiro Hosoya, Takashi Saito, Tsuyoshi Shimo

International journal of molecular sciences 24 ( 10 ) 2023.5

Language：English Publishing type：Research paper (scientific journal)

A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment is unknown. Here, we analyzed surgically resected oral malignant melanoma specimens and observed that Sonic Hedgehog, Gli1, and Gli2 were highly expressed in tumor cells, vasculatures, and osteoclasts. We established a tumor bone destruction mouse model by inoculating B16 cells into the bone marrow space of the right tibial metaphysis of 5-week-old female C57BL mice. An intraperitoneal administration of GANT61 (40 mg/kg), a small-molecule inhibitor of Gli1 and Gli2, resulted in significant inhibition of cortical bone destruction, TRAP-positive osteoclasts within the cortical bone, and endomucin-positive tumor vessels. The gene set enrichment analysis suggested that genes involved in apoptosis, angiogenesis, and the PD-L1 expression pathway in cancer were significantly altered by the GANT61 treatment. A flow cytometry analysis revealed that PD-L1 expression was significantly decreased in cells in which late apoptosis was induced by the GANT61 treatment. These results suggest that molecular targeting of Gli1 and Gli2 may release immunosuppression of the tumor bone microenvironment through normalization of abnormal angiogenesis and bone remodeling in advanced melanoma with jaw bone invasion.

DOI： 10.3390/ijms24108862

Enzyme-Cleaved Bone Marrow Transplantation Improves the Engraftment of Bone Marrow Mesenchymal Stem Cells. Reviewed International journal

Hotaka Kawai, May Wathone Oo, Kiyofumi Takabatake, Ikue Tosa, Yamin Soe, Htoo Shwe Eain, Sho Sanou, Shigeko Fushimi, Shintaro Sukegawa, Keisuke Nakano, Takarada Takeshi, Hitoshi Nagatsuka

JBMR plus 7 ( 3 ) e10722 2023.3

Language：English Publishing type：Research paper (scientific journal)

Mesenchymal stem cell (MSC) therapy is a promising approach to curing bone diseases and disorders. In treating genetic bone disorders, MSC therapy is local or systemic transplantation of isolated and in vitro proliferated MSC rather than bone marrow transplantation. Recent evidence showed that bone marrow MSC engraftment to bone regeneration has been controversial in animal and human studies. Here, our modified bone marrow transplantation (BMT) method solved this problem. Like routine BMT, our modified method involves three steps: (i) isolation of bone marrow cells from the donor, (ii) whole-body lethal irradiation to the recipient, and (iii) injection of isolated bone marrow cells into irradiated recipient mice via the tail vein. The significant modification is imported at the bone marrow isolation step. While the bone marrow cells are flushed out from the bone marrow with the medium in routine BMT, we applied the enzymes' (collagenase type 4 and dispase) integrated medium to wash out the bone marrow cells. Then, cells were incubated in enzyme integrated solution at 37°C for 10 minutes. This modification designated BMT as collagenase-integrated BMT (c-BMT). Notably, successful engraftment of bone marrow MSC to the new bone formation, such as osteoblasts and chondrocytes, occurs in c-BMT mice, whereas routine BMT mice do not recruit bone marrow MSC. Indeed, flow cytometry data showed that c-BMT includes a higher proportion of LepR+, CD51+, or RUNX2+ non-hematopoietic cells than BMT. These findings suggested that c-BMT is a time-efficient and more reliable technique that ensures the disaggregation and collection of bone marrow stem cells and engraftment of bone marrow MSC to the recipient. Hence, we proposed that c-BMT might be a promising approach to curing genetic bone disorders. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

DOI： 10.1002/jbm4.10722

Novel Artificial Scaffold for Bone Marrow Regeneration: Honeycomb Tricalcium Phosphate. Reviewed International journal

Yasunori Inada, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Qiusheng Shan, Tianyan Piao, Anqi Chang, Hotaka Kawai, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 16 ( 4 ) 2023.2

Language：English Publishing type：Research paper (scientific journal)

Bone marrow is complex structure containing heterogenetic cells, making it difficult to regenerate using artificial scaffolds. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which is a cylindrical scaffold with a honeycomb arrangement of straight pores, and we demonstrated that TCP with 300 and 500 μm pore diameters (300TCP and 500TCP) induced bone marrow structure within the pores. In this study, we examined the optimal scaffold structure for bone marrow with homeostatic bone metabolism using honeycomb TCP. 300TCP and 500TCP were transplanted into rat muscle, and bone marrow formation was histologically assessed. Immunohistochemistry for CD45, CD34, Runt-related transcription factor 2 (Runx2), c-kit single staining, Runx2/N-cadherin, and c-kit/Tie-2 double staining was performed. The area of bone marrow structure, which includes CD45(+) round-shaped hematopoietic cells and CD34(+) sinusoidal vessels, was larger in 300TCP than in 500TCP. Additionally, Runx2(+) osteoblasts and c-kit(+) hematopoietic stem cells were observed on the surface of bone tissue formed within TCP. Among Runx2(+) osteoblasts, spindle-shaped N-cadherin(+) cells existed in association with c-kit(+)Tie-2(+) hematopoietic stem cells on the bone tissue formed within TCP, which formed a hematopoietic stem cell niche similar to as in vivo. Therefore, honeycomb TCP with 300 μm pore diameters may be an artificial scaffold with an optimal geometric structure as a scaffold for bone marrow formation.

DOI： 10.3390/ma16041393

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